Substituted pyrrolidinone as inhibitors of hepatitis c ns5b polymerase, the pharmaceutical composition thereof and their therapeutic use

Abstract

The present invention concerns a substituted pyrrolidinone of the following formula I or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof: (I), for the treatment of hepatitis C.

1 .- 14 . (canceled) 
     
     
         15 . A method to treat hepatitis C comprising the administration to a person in need thereof of an effective amount of a compound of the following formula I or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof: 
       
         
           
           
               
               
           
         
         in which 
         n is an integer chosen between 0, 1 or 2; 
         m is an integer chosen between 0, 1, 2 or 3; 
         C═Z represents CH 2  or 
         Z represents an oxygen atom, a —CH—R group or a —N—OR group, in which R represents an hydrogen atom, a C 1 -C 6  alkyl group, a C 3 -C 6  cycloalkyl group, a 3-6 members heterocyclic group containing one or two heteroatoms selected in the group consisting of oxygen, nitrogen and sulfur atom, a (C 1 -C 6  alkyl)COOH group, a (C 1 -C 6  alkyl)O(C 1 -C 6  alkyl) group or a O-protecting group; 
         R1 represents:
 a phenyl group, or 
 a 5-9-members heteroaryl group containing one, two or three heteroatoms selected in the group consisting of oxygen, nitrogen and sulfur atom, 
 
         the phenyl group and the heteroaryl group being optionally substituted by:
 a halogen atom; 
 a phenyl group; 
 a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atomor by one or more OH group; 
 a O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkyl-phenyl-O—(C 1 -C 6 )alkyl group; 
 a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkylCONR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 a —O—(C 1 -C 6 )alkylCOOH group; 
 a 5-, 6- or 7-members heterocyclic group containing one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; or 
 a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 
         R2 represents:
 a hydrogen atom if n≠0, or 
 a phenyl group, or 
 a 5-6-members heteroaryl group containing one, two or three heteroatom (s) selected in the group consisting of oxygen, sulfur and nitrogen atom, or 
 a benzodioxyl group or 
 a C 3 -C 6  cycloalkyl group 
 
         the phenyl group, the cycloalkyl group, the benzodioxyl group and the heteroaryl group being optionally substituted by one or more groups, independently selected among:
 a halogen atom; 
 a —OH group; 
 a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; 
 a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; 
 a phenyl group; 
 a —O-phenyl group; 
 a —CN group; 
 a —NO 2  group; 
 a —COOH group; 
 a —COO(C 1 -C 6  alkyl) group; 
 a —C 2 -C 6  alkenyl group; 
 a —O—(C 2 -C 6 )alkenyl group; 
 a —CONR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 a —O-(6-members heterocyclic) group in which the heterocyclic group contains one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; 
 a —O—((C 1 -C 6 )alkyl) 46 -members heterocyclic) group in which the heterocyclic group contains one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; 
 a —O—((C 1 -C 6 )alkyl)-NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; and 
 a 6-members heterocyclic group containing one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom, the heterocyclic group being optionally substituted by a ((C 1 -C 6 )alkyl)-NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 
         X represents a nitrogen atom and Y represents a —C—R4 group or 
         X represents a —C—R5 group and Y represents a nitrogen atom or 
         X represents a —C—R5 group and Y represents a —C—R4 group, 
         in which: 
         R4 and R5 represent, independently of each other
 a hydrogen atom; 
 a halogen atom; 
 a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; 
 a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; 
 a —COOH group; 
 a —COO(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; 
 a —CN group; 
 a phenyl group; 
 a —S-phenyl-NO 2  group; 
 a —SO 2 -phenyl-NO 2  group; 
 a —SO 2 —(C 1 -C 6 )alkyl group; 
 a —SO 2 -aryl group; 
 a —SO 2 —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 a —SO 2 -(6-members heterocyclic) group containing one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; 
 a —SO 2 —NH-aryl group; 
 a 6-members heterocyclic group containing one or two heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; or 
 a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 
         or R4 and R5 form together with the carbon to which they are bonded a phenyl group optionally substituted by an halogen atom; 
         R3 represents:
 a —OH group or 
 a —O—(C 1 -C 6 )alkyl group or 
 a —O—C═O—(C 1 -C 6 alkyl) group or 
 a —NHR 5  group in which R 5  represents a hydrogen or a (C 1 -C 6 alkyl) group, 
 a NH—C═OR 7  in which R 7  represents a (C 1 -C 6 alkyl) group or 
 a —NHSO 2 R 6  group in which R 6  represents a hydrogen atom or a (C 1 -C 6 alkyl) group. 
 
       
     
     
         16 . The method according to  claim 15 , wherein n=0. 
     
     
         17 . The method according to  claim 15 , wherein m=0. 
     
     
         18 . The method according to  claim 15 , wherein Z represents an oxygen atom or a —N—OR group in which R represent a C 1 -C 6  alkyl group, a (C 1 -C 6  alkyl)O(C 1 -C 6  alkyl) group or a (C 1 -C 6  alkyl)COOH group. 
     
     
         19 . The method according to  claim 15 , wherein R1 represents:
 a phenyl group, or   a 5-9-members heteroaryl group containing one, two or three heteroatoms selected in the group consisting of oxygen, nitrogen and sulfur atom,   the phenyl group and the heteroaryl group being optionally substituted in the para position by:
 a halogen atom; 
 a phenyl group; 
 a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atomor by one or more OH group; 
 a O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkyl-phenyl-O—(C 1 -C 6 )alkyl group; 
 a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; 
 a —O—(C 1 -C 6 )alkylCONR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; 
 a —O—(C 1 -C 6 )alkylCOOH group; 
 a 5-, 6- or 7-members heterocyclic group containing one, two or three hetero atoms selected in the group consisting of nitrogen, sulfur and oxygen atom; or 
 a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group. 
   
     
     
         20 . The method according to  claim 15 , wherein R1 represents a phenyl group, optionally substituted by a halogen atom; a phenyl group; a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom or by one or more OH group; a O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a —O—(C 1 -C 6 )alkyl-phenyl-O—(C 1 -C 6 )alkyl group; a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; a —O—(C 1 -C 6 )alkylCONR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; a —O—(C 1 -C 6 )alkylCOOH group; a 5-, 6- or 7-members heterocyclic group containing one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; or a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group. 
     
     
         21 . The method according to  claim 15 , wherein R2 represents a phenyl group, optionally substituted, by one or more groups independently selected among a halogen atom; a —OH group; a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; a phenyl group; a —O-phenyl group; a —CN group; a —NO 2  group; a —COOH group; a —COO(C 1 -C 6  alkyl) group; a —C 2 -C 6  alkenyl group; a —O—(C 2 -C 6 )alkenyl group; a —CONR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; a —O-(6-members heterocyclic) group in which the heterocyclic group contains one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; a —O—((C 1 -C 6 )alkyl)-(6-members heterocyclic) group in which the heterocyclic group contains one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; a —O—((C 1 -C 6 )alkyl)-NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; and a 6-members heterocyclic group containing one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom the heterocyclic group being optionally substituted by a ((C 1 -C 6 )alkyl)-NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group. 
     
     
         22 . The method according to  claim 15 , wherein X represents a nitrogen atom and Y represents a —C—R4 group or X represents a —C—R5 group and Y represents a nitrogen atom in which R4 and R5 represent, independently of each other, a hydrogen atom; a halogen atom; a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a —COOH group; a —COO(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a —CN group; a phenyl group; a 6-members heterocyclic group containing one or two heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; or a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group. 
     
     
         23 . The method according to  claim 15 , wherein X represents a —C—R5 group and Y represents a —C—R4 group in which:
 R4 and R5 represent, independently of each other a hydrogen atom; a halogen atom; a C 1 -C 6  alkyl group optionally substituted by one or more halogen atom; a C 3 -C 6  cycloalkyl group optionally substituted by one or more halogen atom; a —O—(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a —COOH group; a —COO(C 1 -C 6 )alkyl group in which the alkyl group is optionally substituted by one or more halogen atom; a —CN group; a —SO 2 -phenyl-NO 2  group; a —SO 2 —(C 1 -C 6 )alkyl group; a —SO 2 -aryl group; a —SO 2 —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; a —SO 2 -(6-members heterocyclic) group containing one, two or three heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; a —SO 2 —NH-aryl group; a 6-members heterocyclic group containing one or two heteroatoms selected in the group consisting of nitrogen, sulfur and oxygen atom; or a —NR′R″ group in which R′ and R″ represent independently of each other a hydrogen atom or a C 1 -C 6  alkyl group; or R4 and R5 form together with the carbon on which they are bonded a phenyl group optionally substituted by an halogen atom. 
 
     
     
         24 . The method according to  claim 15 , wherein R3 represents a —OH group. 
     
     
         25 . The method according to  claim 15 , wherein the compound of formula (I) is chosen from the group consisting of the compounds of formula I-36 and 39-133. 
     
     
         26 . A compound of formula 1, 2, 4-9, 11-27, 29, 30, 33-36, 39, 41-50 and 125-131 or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof. 
     
     
         27 . A pharmaceutical composition comprising a compound according to  claim 26  or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof and a pharmaceutically acceptable diluent or carrier. 
     
     
         28 . A method to treat or prevent a viral infection comprising the administration to a person in need thereof of an effective amount of a composition according to  claim 27  or a compound according to  claim 26  or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof. 
     
     
         29 . A method to treat hepatitis C comprising the administration to a person in need thereof of an effective amount of a composition according to  claim 27  or a compound according to  claim 26  or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof. 
     
     
         30 . A method to treat hepatitis C comprising the simultaneous, separate or sequential administration to a person in need thereof of an effective amount of a compound of formula (I) as defined in  claim 15  or a salt, solvate, tautomer, isotope, enantiomer, diastereoisomer or racemic mixture thereof and at least another antiviral agent. 
     
     
         31 . The method according to  claim 30 , wherein the other antiviral agent is selected in the group consisting of ribavirin, interferon, inhibitors of HCV helicase, inhibitors of HCV protease, inhibitors of HCV NS4A, inhibitors of HCV NS5B, inhibitors of HCV NS5A, inhibitors of HCV polymerase, HBV inhibitors and mixture thereof. 
     
     
         32 . The method according to  claim 30 , wherein the person has the HIV disease.